scholarly journals Biosynthesis of the redox cofactor mycofactocin comprises oligoglycosylation by MftF in Mycolicibacterium smegmatis

2019 ◽  
Author(s):  
Luis Peña-Ortiz ◽  
Ana Patrícia Graça ◽  
Huijuan Guo ◽  
Daniel Braga ◽  
Tobias G. Köllner ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Metabolic Profiling ◽  
Drug Target ◽  
Structure Elucidation ◽  
Potential Drug Target ◽  
Potential Drug ◽  
Alcohol Metabolism ◽  
Future Studies ◽  
Mycobacterial Diseases

AbstractMycofactocin (MFT) is a redox cofactor involved in alcohol metabolism of mycobacteria including Mycobacterium tuberculosis. In recent years, a preliminary biosynthetic model of MFT has been established by in-vitro studies, while the final structure of MFT remained elusive. Here, we report the discovery of MFT by metabolomics and establish a model of its biosynthesis in Mycolicibacterium smegmatis. Structure elucidation revealed that MFT is decorated with up to nine β-1,4-linked glucose residues. Dissection of biosynthetic genes demonstrated that the oligoglycosylation is catalyzed by the glycosyltransferase MftF. Furthermore, we confirm the cofactor function of MFT by activity-based metabolic profiling using the carveol dehydrogenase LimC and show that the MFT pool expands during cultivation on ethanol. Our results close an important gap of knowledge, will guide future studies into the physiological roles of MFT in bacteria and may inspire its utilization as a biomarker or potential drug target to combat mycobacterial diseases.

scholarly journals A causal role for TRESK loss of function in migraine mechanisms

Brain ◽  
2019 ◽  
Vol 142 (12) ◽  
pp. 3852-3867 ◽  
Author(s):  
Philippa Pettingill ◽  
Greg A Weir ◽  
Tina Wei ◽  
Yukyee Wu ◽  
Grace Flower ◽  
...  
Keyword(s):  
Potassium Channel ◽  
Drug Target ◽  
Causal Role ◽  
Potential Drug Target ◽  
Potential Drug ◽  
Loss Of Function

The two-pore potassium channel TRESK is a potential drug target in pain and migraine. Pettingill et al. show that the F139WfsX2 mutation causes TRESK loss of function and hyperexcitability in nociceptors derived from iPSCs of patients with migraine. Cloxyquin, a TRESK activator, reverses migraine-relevant phenotypes in vitro and in vivo.

scholarly journals Inhibition of Glutamine Synthetase: A Potential Drug Target in Mycobacterium tuberculosis

Molecules ◽  
2014 ◽  
Vol 19 (9) ◽  
pp. 13161-13176 ◽  
Author(s):  
Sherry Mowbray ◽  
Muthu Kathiravan ◽  
Abhishek Pandey ◽  
Luke Odell
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Glutamine Synthetase ◽  
Drug Target ◽  
Potential Drug Target ◽  
Potential Drug

scholarly journals Chemical validation of Mycobacterium tuberculosis phosphopantetheine adenylyltransferase using fragment linking and CRISPR interference

2020 ◽  
Author(s):  
Jamal El Bakali ◽  
Michal Blaszczyk ◽  
Joanna C. Evans ◽  
Jennifer A. Boland ◽  
William J. McCarthy ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Crystal Structures ◽  
Active Site ◽  
Drug Target ◽  
Potential Drug Target ◽  
Biosynthesis Pathway ◽  
Potential Drug ◽  
Antimicrobial Drugs ◽  
X Ray ◽  
Crispr Interference

AbstractThe coenzyme A (CoA) biosynthesis pathway has attracted attention as a potential target for much-needed novel antimicrobial drugs, including for the treatment of tuberculosis (TB), the lethal disease caused by Mycobacterium tuberculosis (Mtb). Seeking to identify the first inhibitors of Mtb phosphopantetheine adenylyltransferase (MtbPPAT), the enzyme that catalyses the penultimate step in CoA biosynthesis, we performed a fragment screen. In doing so, we discovered three series of fragments that occupy distinct regions of the MtbPPAT active site, presenting a unique opportunity for fragment linking. Here we show how, guided by X-ray crystal structures, we could link weakly-binding fragments to produce an active site binder with a KD < 20 μM and on-target anti-Mtb activity, as demonstrated using CRISPR interference. This study represents a big step toward validating MtbPPAT as a potential drug target and designing a MtbPPAT-targeting anti-TB drug.Abstract Figure

Isochorismate Synthase (MenF)-3D Prediction in Mycobacterium Tuberculosis: A Potential Drug Target

2017 ◽  
Vol 5 (2) ◽  
pp. 117
Author(s):  
Leeladhar Sammatur ◽  
C.M. Anuradha ◽  
Srinivasulu Cheemanapalli ◽  
P. Madhusudana ◽  
Suresh Kumar Chitta
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Drug Target ◽  
Potential Drug Target ◽  
Potential Drug ◽  
Isochorismate Synthase

Proteome-wide subtractive approach to prioritize a hypothetical protein of XDR-Mycobacterium tuberculosis as potential drug target

2019 ◽  
Vol 41 (11) ◽  
pp. 1281-1292 ◽  
Author(s):  
Reaz Uddin ◽  
Quratulain Nehal Siddiqui ◽  
Muhammad Sufian ◽  
Syed Sikander Azam ◽  
Abdul Wadood
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Drug Target ◽  
Hypothetical Protein ◽  
Potential Drug Target ◽  
Potential Drug
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